Figure 6

Model of initial lesion sensing by glycosylases. Undamaged DNA is shown in grey, damaged DNA in black. The base lesion destabilizes base pairing and deforms DNA, as shown exaggerated to better visualize the point. DNA destabilization by the lesion lowers the energy barrier for base breathing (flipped lesion base shown in red). In our model, DNA bendability at target lesions matches the degree of DNA bending in the lesion search complex (SC) conformation of the corresponding glycosylase. This results in passive (energetically favorable) DNA bending by the enzymes at a DNA damage versus active (energy consuming) bending of undamaged DNA (grey arrows). The different energy requirements of DNA bending at target lesions and at undamaged sites lead to a dissociation of the glycosylase from undamaged DNA sites (beige arrows) and stabilized binding at potential target sites. The resulting enhanced residence time at target sites allows the glycosylase to test these bases in the interrogation complex, in which the DNA is further bent to support base flipping into the enzyme catalytic site pocket.